Small molecule inhibitors of kynurenine-3-monooxygenase

ABSTRACT

The present invention relates to compounds of Formula I below and their tautomers or pharmaceutically acceptable salts, compositions and methods of uses thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims benefit under 35 U.S.C. §119(e) of U.S.Provisional Application Ser. No. 60/838,446, filed Aug. 16, 2006, whichis hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates generally to benzenesulfonamide compounds andtheir use as inhibitors of kynurenine-3-monooxygenase.

BACKGROUND OF THE INVENTION

Tryptophan is metabolized in mammals via the kynurenine pathway to yieldthree neuroactive substances, 3-hydroxykynurenine, kynurenic acid andquinolinic acid. Kynurenic acid has neuroprotective activities in vivowhile 3-hydroxykynurenine and quinolinic acid are neurotoxic. Studieshave shown that 3-hydroxykynurenine and quinolinic acid are causative orcontribute to delayed neurological damages and are associated with avariety of human diseases including neurodegenerative disorders andpsychiatric diseases. Pharmacological intervention aimed at blocking3-hydroxykynurenine and quinolinic acid synthesis and/or increasingkynurenic acid formation have been attempted in treatment ofneurological diseases and their peripheral indications, such asdiabetes.

Kynurenine-3-monooxygenase (KMO) is an enzyme in the tryptophandegradation pathway that catalyzes the conversion of kynurenine into3-hydroxykynurenine which is a precursor of the neurotoxin quinolinicacid. Therefore, compounds which act as inhibitors of KMO are ofparticular interest since they block the metabolism toward quinolinicacid and at the same time, increase the formation of neuroprotectivemetabolite kynurenic acid.

Inhibitors of KMO have been known in the art. For example, U.S. Pat. No.5,877,193 describes N-(4-arylthiazol-2-yl)-sulfonamide derivatives fortreating neurodegenerative disorders resulting from an activation of theimmune system.

There remains a need for compounds that are effective inhibitors of KMOand can be used in treating neurodegenerative disorders. Compounds thatinhibit KMO and can thus be used to treat and prevent KMO-associateddisorders including neurodegenerative disorders are provided herein.

SUMMARY OF THE INVENTION

This invention is directed to novel compounds, pharmaceuticalcompositions and methods of using the compounds to inhibit KMO.

In one aspect of the invention, there are provided compounds of FormulaI:

wherein:

A is selected from the group consisting of aryl and heteroaryl;

Ar¹ and Ar² are independently selected from the group consisting ofaryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R³ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, halo, amino, substituted amino,alkylthio, substituted alkylthio, substituted sulfonyl, substitutedsulfinyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

n is an integer from 0 to 3;

or their tautomers and/or a pharmaceutically acceptable salt thereof,

with the proviso that A is not 1,3-thiazol-2-yl.

In some embodiments of the invention, there are provided compounds ofFormula II:

wherein:

T and W independently are selected from the group consisting of N, NR³,S, S(O), S(O)₂, O, and CR³ and U is selected from the group consistingof N, NR³, S, S(O), S(O)₂, and O with the proviso that no more than oneof T, U, and W are S, S(O), S(O)₂, and O;

R¹ and R² independently are selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, substitutedamino, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino,carboxyl, carboxyl ester, cyano, halo, hydroxyl, acyl, nitro, mercapto,alkylthio, substituted alkylthio, substituted sulfonyl, substitutedsulfonyloxy, substituted sulfinyl, and aminocarbonyl, or R¹ and R² jointogether to form a ring selected from the group consisting of C₅-C₇cycloalkyl, substituted C₅-C₇ cycloalkyl, C₅-C₇ heterocycloalkyl,substituted C₅-C₇ heterocycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl;

R³ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, halo, amino, substituted amino,alkylthio, substituted alkylthio, substituted sulfonyl, substitutedsulfinyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, substitutedamino, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino,carboxyl, carboxyl ester, cyano, halo, hydroxyl, acyl, nitro, mercapto,alkylthio, substituted alkylthio, substituted sulfonyl, substitutedsulfonyloxy, substituted sulfinyl, and aminocarbonyl, or R⁴ and R⁵ jointogether to form a ring selected from the group consisting of C₅-C₇cycloalkyl, substituted C₅-C₇ cycloalkyl, C₅-C₇ heterocycloalkyl,substituted C₅-C₇ heterocycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl; and

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl; substituted aryl, heteroaryl and substituted heteroaryl;

or their tautomers and/or a pharmaceutically acceptable salt thereof.

In a particular embodiment, there are provided compounds of Formula IIaor their tautomers and/or a pharmaceutically acceptable salt thereof:

wherein X is S or NR⁹ where R⁹ is alkyl or substituted alkyl; and R¹,R², R⁴, R⁵, and R⁶ are as defined herein.

In another particular embodiment, there are provided compounds ofFormula IIb or their tautomers and/or a pharmaceutically acceptable saltthereof:

wherein X¹ is S or NH; and R¹, R², R⁴, R⁵, and R⁶ are as defined herein.

In another particular embodiment, there are provided compounds ofFormula IIc or their tautomers and/or a pharmaceutically acceptable saltthereof:

wherein X² is O or NR⁹ where R⁹ is alkyl or substituted alkyl; and R¹,R², R⁴, R⁵, and R⁶ are as defined herein.

In another particular embodiment, there are provided compounds ofFormula IId or their tautomers and/or a pharmaceutically acceptable saltthereof:

wherein X³ is S or NR⁹ where R⁹ is alkyl or substituted alkyl; and R¹,R², R⁴, R⁵, and R⁶ are as defined herein.

In another particular embodiment, there are provided compounds ofFormula IIe or their tautomers and/or a pharmaceutically acceptable saltthereof:

wherein X⁵ is O, S, NH, or NR³; and R¹, R², R³, R⁴, R⁵, and R⁶ are asdefined herein.

In another particular embodiment, there are provided compounds ofFormula IIf or their tautomers and/or a pharmaceutically acceptable saltthereof:

wherein X⁶ is O, S, NH, or NR³; and R¹, R², R³, R⁴, R⁵, and R⁶ are asdefined herein.

In another particular embodiment, there are provided compounds ofFormula IIg or their tautomers and/or a pharmaceutically acceptable saltthereof:

wherein X⁷ is O, S, NH, or NR³; and R¹, R², R³, R⁴, R⁵, and R⁶ are asdefined herein.

In some embodiments of the invention, there are provided compounds ofFormula III:

X⁴ and Y are independently selected from the group consisting of N andCR⁸;

Ar¹ and Ar² are independently selected from the group consisting ofaryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R⁷ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, amino, substituted amino, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester,cyano, halo, hydroxyl, acyl, nitro, mercapto, alkylthio, substitutedalkylthio, substituted sulfonyl, substituted sulfonyloxy, substitutedsulfinyl, and aminocarbonyl, or 2 or more R⁷ join to form a ring whenm>1, where the ring is selected from the group consisting of C₅-C₇cycloalkyl, substituted C₅-C₇ cycloalkyl, C₅-C₇ heterocycloalkyl,substituted C₅-C₇ heterocycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl;

m is an integer from 0 to 3; and

R⁸ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, halo, amino, substituted amino, aryl, substituted aryl,heteroaryl, and substituted heteroaryl;

or their tautomers and/or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, there are provided compounds ofFormula IIIa:

wherein X⁹ is N or CH; and R¹, R², R⁴, R⁵, and R⁶ are as defined herein.

In some embodiments of the invention, there are provided compounds ofFormula IIIb:

wherein X¹⁰ is N or CH; and R¹, R², R⁴, R⁵, and R⁶ are as definedherein.

In some embodiments of the invention, there are provided compounds ofFormula IIIc:

wherein R¹, R², R⁴, R⁵, and R⁶ are as defined herein.

In some embodiments of the invention, there are provided compounds ofFormula IIId:

wherein R¹, R², R⁴, R⁵, and R⁶ are as defined herein.

In another aspect of the invention, the invention providespharmaceutical compositions comprising one or more compounds of FormulaI, II, IIa, IIb, IIc, IId, IIe, IIf, IIg, III, IIIa, IIIb, IIIc, or IIIdand a pharmaceutically acceptable excipient.

In one of its method aspects, this invention is directed to a method forinhibiting activity of kynurenine-3-monooxygenase activity which methodcomprises contacting cells (including neurons/microglia/invadingmacrophages) with an effective amount of one or more compounds ofFormula I, II, IIa, IIb, IIc, IId, IIe, IIf, IIg, III, IIIa, IIIb, IIIc,or IIId.

In another of its method aspects, this invention is directed to a methodfor treating a disease mediated at least in part bykynurenine-3-monooxygenase which method comprises administering to apatient an effective amount of one or more compounds of Formula I or apharmaceutical composition comprising a pharmaceutically acceptableexcipient and one or more compounds of Formula I, II, IIa, IIb, IIc,IId, IIe, IIf, IIg, III, IIIa, IIIb, IIIc, or IIId.

Diseases mediated at least in part by kynurenine-3-monooxygenase includethose selected from the group consisting of Huntington's disease andother polyglutamine disorders such as spinocerebellar ataxias,Alzheimer's disease, Parkinson's disease, high-pressure neurologicalsyndrome, dystonia, olivopontocerebellar atrophy, amyotrophic lateralsclerosis, multiple sclerosis, epilepsy, consequences of stroke,cerebral ischemia, hypoxia, multi-infarct dementia, consequences ofcerebral trauma or damage, damage to the spinal cord, AIDS-dementiacomplex, viral or bacterial meningitis, general central nervous system(CNS) infections such as viral, bacterial or parasites, for example,poliomyelitis, Lyme disease (Borrelia burgdorferi infection) andmalaria, cancers with cerebral localization, Tourette's syndrome,hepatic encephalopathy, systemic lupus, analgesia and opiate withdrawalsymptoms, feeding behaviour, schizophrenia, chronic anxiety, depressivedisorders, disorders of the developing or aged brain, diseases ofaddiction, diabetes, and complications thereof. The compounds of thisinvention may also influence synaptogenesis after brain injury. Thecompounds also may influence memory.

In another of its method aspects, this invention is directed to anarticle of manufacture for use to inhibit kynurenine-3-monooxygenase fortreating a disease mediated at least in part bykynurenine-3-monooxygenase comprising a composition comprising apharmaceutically acceptable excipient and compound of the Formula I, II,IIa, IIb, IIc, IId, IIe, IIf, IIg, III, IIIa, IIIb, IIIc, or IIId, asprovided herein. The diseases mediated at least in part bykynurenine-3-monooxygenase are as provided herein. In one embodiment,the article of manufacture further comprises a label with instructionsfor using the composition to treat a disease mediated at least in partby kynurenine-3-monooxygenase.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this application, the text refers to various embodiments ofthe present compounds, compositions, and methods. The variousembodiments described are meant to provide a variety of illustrativeexamples and should not be construed as descriptions of alternativespecies. Rather, it should be noted that the descriptions of variousembodiments provided herein may be of overlapping scope. The embodimentsdiscussed herein are merely illustrative and are not meant to limit thescope of the present invention.

1. Definitions

As used herein, the following definitions shall apply unless otherwiseindicated.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms.This term includes, by way of example, linear and branched hydrocarbylgroups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—),isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—),sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl(CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

“Alkenyl” refers to straight or branched hydrocarbyl groups having from2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having atleast 1 and preferably from 1 to 2 sites of vinyl (>C═C<) unsaturation.Such groups are exemplified, for example, by vinyl, allyl, andbut-3-en-1-yl. Included within this term are the cis and trans isomersor mixtures of these isomers.

“Alkynyl” refers to straight or branched monovalent hydrocarbyl groupshaving from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms andhaving at least 1 and preferably from 1 to 2 sites of acetylenic (—C≡C—)unsaturation. Examples of such alkynyl groups include acetylenyl(—C≡CH), and propargyl (—CH₂C≡CH).

“Substituted alkyl” refers to an alkyl group having from 1 to 5,preferably 1 to 3, or more preferably 1 to 2 substituents selected fromthe group consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein.

Preferred substituted alkyl groups included halogenated alkyl groups andparticularly halogenated methyl groups such as trifluoromethyl,difluromethyl, fluoromethyl and the like.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein and with the proviso thatany hydroxy or thiol substitution is not attached to a vinyl(unsaturated) carbon atom.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein and with the proviso thatany hydroxyl or thiol substitution is not attached to an acetyleniccarbon atom.

“Alkoxy” refers to the group —O-alkyl wherein alkyl is defined herein.Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

“Substituted alkoxy” refers to the group —O-(substituted alkyl) whereinsubstituted alkyl is defined herein. Preferred substituted alkyl groupsin —O-(substituted alkyl) include halogenated alkyl groups andparticularly halogenated methyl groups such as trifluoromethyl,difluromethyl, fluoromethyl and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—,substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein. Acyl includes the “acetyl” group CH₃C(O)—.

“Acylamino” refers to the groups —NR³⁰C(O)alkyl, —NR³⁰C(O)substitutedalkyl, —NR³⁰C(O)cycloalkyl, —NR³⁰C(O)substituted cycloalkyl,—NR³⁰C(O)alkenyl, —NR³⁰C(O)substituted alkenyl, —NR³⁰C(O)alkynyl,—NR³⁰C(O)substituted alkynyl, —NR³⁰C(O)aryl, —NR³⁰C(O)substituted aryl,—NR³⁰C(O)heteroaryl, —NR³⁰C(O)substituted heteroaryl,—NR³⁰C(O)heterocyclic, and —NR³⁰C(O)substituted heterocyclic wherein R³⁰is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, heteroaryl-C(O)O—, substitutedheteroaryl-C(O)O—, heterocyclic-C(O)O—, and substitutedheterocyclic-C(O)O— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR³¹R³² where R³¹ and R³² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, and substituted sulfonyl and wherein R³¹ and R³² areoptionally joined, together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group, provided that R³¹ andR³² are both not hydrogen, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein. When R³¹ is hydrogen and R³² is alkyl, the substituted aminogroup is sometimes referred to herein as alkylamino. When R³¹ and R³²are alkyl, the substituted amino group is sometimes referred to hereinas dialkylamino. When referring to a monosubstituted amino, it is meantthat either R³¹ or R³² is hydrogen but not both. When referring to adisubstituted amino, it is meant that neither R³¹ nor R³² are hydrogen.

“Aminocarbonyl” refers to the group —C(O)NR³³R³⁴ where R³³ and R³⁴ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkylheteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R³³ and R³⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminothiocarbonyl” refers to the group —C(S)NR³³R³⁴ where R³³ and R³⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R³³ and R³⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminocarbonylamino” refers to the group —NR³⁰C(O)NR³³R³⁴ where R³⁰ ishydrogen or alkyl and R³³ and R³⁴ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R³³ andR³⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminothiocarbonylamino” refers to the group —NR³⁰C(S)NR³³R³⁴ where R³⁰is hydrogen or alkyl and R³³ and R³⁴ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R³³ andR³⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminocarbonyloxy” refers to the group —O—C(O)NR³³R³⁴ where R³³ and R³⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R³³ and R³⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonyl” refers to the group —SO₂NR³³R³⁴ where R³³ and R³⁴ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R³³ and R³⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonyloxy” refers to the group —O—SO₂NR³³R³⁴ where R³³ and R³⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R³³ and R³⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonylamino” refers to the group —NR³⁰—SO₂NR³³R³⁴ where R³⁰ ishydrogen or alkyl and R³³ and R³⁴ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R³³ andR³⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Amidino” refers to the group —C(═NR³⁵)NR³³R³⁴ where R³³, R³⁴, and R³⁵are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R³³ and R³⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) which condensed rings may ormay not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the pointof attachment is at an aromatic carbon atom. Preferred aryl groupsinclude phenyl and naphthyl.

“Substituted aryl” refers to aryl groups which are substituted with 1 to5, preferably 1 to 3, or more preferably 1 to 2 substituents selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino,substituted guanidino, halo, hydroxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein.

“Aryloxy” refers to the group —O-aryl, where aryl is as defined herein,that includes, by way of example, phenoxy and naphthoxy.

“Substituted aryloxy” refers to the group —O-(substituted aryl) wheresubstituted aryl is as defined herein.

“Arylthio” refers to the group —S-aryl, where aryl is as defined herein.

“Substituted arylthio” refers to the group —S-(substituted aryl), wheresubstituted aryl is as defined herein.

“Carbonyl” refers to the divalent group —C(O)— which is equivalent to—C(═O)—.

“Carboxy” or “carboxyl” refers to —COOH or salts thereof.

“Carboxyl ester” or “carboxy ester” refers to the groups —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl,—C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl,—C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

“(Carboxyl ester)amino” refers to the group —NR³⁰—C(O)O-alkyl,—NR³⁰—C(O)O-substituted alkyl, —NR³⁰—C(O)O-alkenyl,—NR³⁰—C(O)O-substituted alkenyl, —NR³⁰—C(O)O-alkynyl,—NR³⁰—C(O)O-substituted alkynyl, —NR³⁰—C(O)O-aryl,—NR³⁰—C(O)O-substituted aryl, —NR³⁰—C(O)O-cycloalkyl,—NR³⁰—C(O)O-substituted cycloalkyl, —NR³⁰—C(O)O-heteroaryl,—NR³⁰—C(O)O-substituted heteroaryl, —NR³⁰—C(O)O-heterocyclic, and—NR³⁰—C(O)O-substituted heterocyclic wherein R³⁰ is alkyl or hydrogen,and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“(Carboxyl ester)oxy” refers to the group —O—C(O)O-alkyl,—O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl, —O—C(O)O-substitutedalkenyl, —O—C(O)O-alkynyl, —O—C(O)O-substituted alkynyl, —O—C(O)O-aryl,—O—C(O)O-substituted aryl, —O—C(O)O-cycloalkyl, —O—C(O)O-substitutedcycloalkyl, —O—C(O)O-heteroaryl, —O—C(O)O-substituted heteroaryl,—O—C(O)O-heterocyclic, and —O—C(O)O-substituted heterocyclic whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Cyano” refers to the group —C≡N.

“Cycloalkyl” refers to a saturated or unsaturated but nonaromatic cyclicalkyl groups of from 3 to 10 carbon atoms having single or multiplecyclic rings including fused, bridged, and spiro ring systems. Examplesof suitable cycloalkyl groups include, for instance, adamantyl,cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more therings can be aryl, heteroaryl, or heterocyclic provided that the pointof attachment is through the non-aromatic, non-heterocyclic ringsaturated carbocyclic ring.“Substituted cycloalkyl” refers to acycloalkyl group having from 1 to 5 or preferably 1 to 3 substituentsselected from the group consisting of oxo, thione, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substitutedamino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino,substituted guanidino, halo, hydroxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein.

“Cycloalkyloxy” refers to —O-cycloalkyl.

“Substituted cycloalkyloxy” refers to —O-(substituted cycloalkyl).

“Cycloalkylthio” refers to —S-cycloalkyl.

“Substituted cycloalkylthio” refers to —S-(substituted cycloalkyl).

“Guanidino” refers to the group —NHC(═NH)NH₂.

“Substituted guanidino” refers to —NR³⁶C(═NR³⁶)N(R³⁶)₂ where each R³⁶ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and two R³⁶groups attached to a common guanidino nitrogen atom are optionallyjoined together with the nitrogen bound thereto to form a heterocyclicor substituted heterocyclic group, provided that at least one R³⁶ is nothydrogen, and wherein said substituents are as defined herein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is fluoro or chloro.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atomsand 1 to 4 heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur within the ring. Such heteroaryl groups can have asingle ring (e.g., pyridinyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl) wherein the condensed rings may ormay not be aromatic and/or contain a heteroatom provided that the pointof attachment is through an atom of the aromatic heteroaryl group. Inone embodiment, the nitrogen and/or the sulfur ring atom(s) of theheteroaryl group are optionally oxidized to provide for the N-oxide(N→O), sulfinyl, or sulfonyl moieties. Preferred heteroaryls includepyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to2 substituents selected from the group consisting of the same group ofsubstituents defined for substituted aryl.

“Heteroaryloxy” refers to —O-heteroaryl.

“Substituted heteroaryloxy” refers to the group —O-(substitutedheteroaryl).

“Heteroarylthio” refers to the group —S-heteroaryl.

“Substituted heteroarylthio” refers to the group —S-(substitutedheteroaryl).

“Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl”refers to a saturated or partially saturated, but not aromatic, grouphaving from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatomsselected from the group consisting of nitrogen, sulfur, or oxygen.Heterocycle encompasses single ring or multiple condensed rings,including fused bridged and spiro ring systems. In fused ring systems,one or more the rings can be cycloalkyl, aryl or heteroaryl providedthat the point of attachment is through the non-aromatic ring. In oneembodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic groupare optionally oxidized to provide for the N-oxide, sulfinyl, sulfonylmoieties.

“Substituted heterocyclic” or “substituted heterocycloalkyl” or“substituted heterocyclyl” refers to heterocyclyl groups that aresubstituted with from 1 to 5 or preferably 1 to 3 of the samesubstituents as defined for substituted cycloalkyl.

“Heterocyclyloxy” refers to the group —O-heterocycyl.

“Substituted heterocyclyloxy” refers to the group —O-(substitutedheterocycyl).

“Heterocyclylthio” refers to the group —S-heterocycyl.

“Substituted heterocyclylthio” refers to the group —S-(substitutedheterocycyl).

Examples of heterocycle and heteroaryls include, but are not limited to,azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, indolizine, isoindole, indole, dihydroindole, indazole,purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,and tetrahydrofuranyl.

“Nitro” refers to the group —NO₂.

“Oxo” refers to the atom (═O) or (—O⁻).

“Spiro ring systems” refers to bicyclic ring systems that have a singlering carbon atom common to both rings.

“Sulfinyl” refers to the divalent group —SO—.

“Sulfonyl” refers to the divalent group —S(O)₂—.

“Substituted sulfonyl” refers to the group —SO₂-alkyl, —SO₂-substitutedalkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl,—SO₂-substituted cycloalkyl, —SO₂-aryl, —SO₂-substituted aryl,—SO₂-heteroaryl, —SO₂-substituted heteroaryl, —SO₂-heterocyclic,—SO₂-substituted heterocyclic, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein. Substituted sulfonyl includes groups such as methyl-SO₂—,phenyl-SO₂—, and 4-methylphenyl-SO₂—. Preferred substituted alkyl groupson the substituted alkyl-SO₂— include halogenated alkyl groups andparticularly halogenated methyl groups such as trifluoromethyl,difluromethyl, fluoromethyl and the like.

“Substituted sulfinyl” refers to the group —SO-alkyl, —SO-substitutedalkyl, —SO-alkenyl, —SO-substituted alkenyl, —SO-cycloalkyl,—SO-substituted cycloalkyl, —SO-aryl, —SO-substituted aryl,—SO-heteroaryl, —SO-substituted heteroaryl, —SO-heterocyclic,—SO-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein. Substituted sulfinyl includes groups such as methyl-SO—,phenyl-SO—, and 4-methylphenyl-SO—. Preferred substituted alkyl groupson the substituted alkyl-SO— include halogenated alkyl groups andparticularly halogenated methyl groups such as trifluoromethyl,difluromethyl, fluoromethyl and the like.

“Sulfonyloxy” or “substituted sulfonyloxy” refers to the group—OSO₂-alkyl, —OSO₂-substituted alkyl, —OSO₂-alkenyl, —OSO₂-substitutedalkenyl, —OSO₂-cycloalkyl, —OSO₂-substituted cycloalkyl, —OSO₂-aryl,—OSO₂-substituted aryl, —OSO₂-heteroaryl, —OSO₂-substituted heteroaryl,—OSO₂-heterocyclic, —OSO₂-substituted heterocyclic, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

“Thioacyl” refers to the groups H—C(S)—, alkyl-C(S)—, substitutedalkyl-C(S)—, alkenyl-C(S)—, substituted alkenyl-C(S)—, alkynyl-C(S)—,substituted alkynyl-C(S)—, cycloalkyl-C(S)—, substitutedcycloalkyl-C(S)—, aryl-C(S)—, substituted aryl-C(S)—, heteroaryl-C(S)—,substituted heteroaryl-C(S)—, heterocyclic-C(S)—, and substitutedheterocyclic-C(S)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Mercapto” or “thiol” refers to the group —SH.

“Formyl” refers to the group —C(O)H.

“Thiocarbonyl” refers to the divalent group —C(S)— which is equivalentto —C(═S)—.

“Thione” refers to the atom (═S).

“Alkylthio” refers to the group —S-alkyl wherein alkyl is as definedherein.

“Substituted alkylthio” refers to the group —S-(substituted alkyl)wherein substituted alkyl is as defined herein. Preferred substitutedalkyl groups on —S-(substituted alkyl) include halogenated alkyl groupsand particularly halogenated methyl groups such as trifluoromethyl,difluromethyl, fluoromethyl and the like.

“Stereoisomer” or “stereoisomers” refer to compounds that differ in thechirality of one or more stereocenters. Stereoisomers includeenantiomers and diastereomers.

“Tautomer” refer to alternate forms of a compound that differ in theposition of a proton, such as enol-keto and imine-enamine tautomers, orthe tautomeric forms of heteroaryl groups containing a ring atomattached to both a ring —NH— moiety and a ring ═N— moiety such aspyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

“Treating” or “treatment” of a disease in a patient refers to 1)preventing the disease from occurring in a patient that is predisposedor does not yet display symptoms of the disease; 2) inhibiting thedisease or arresting its development; or 3) ameliorating or causingregression of the disease.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“alkoxycarbonylalkyl” refers to the group (alkoxy)-C(O)-(alkyl)-.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. In such cases, the maximumnumber of such substituents is three. That is to say that each of theabove definitions is constrained by a limitation that, for example,substituted aryl groups are limited to -substituted aryl-(substitutedaryl)-substituted aryl.

It is understood that the above definitions are not intended to includeimpermissible substitution patterns (e.g., methyl substituted with 5fluoro groups). Such impermissible substitution patterns are well knownto the skilled artisan.

2. Compounds of the Invention

This invention is directed to compounds, compositions and methods ofusing the compounds as inhibitors of KMO and inhibit the KMO activitiesin the brain.

In one aspect, the present invention provides compounds of generalFormula I:

wherein:

A is selected from the group consisting of aryl and heteroaryl;

Ar¹ and Ar² are independently selected from the group consisting ofaryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R³ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, halo, amino, substituted amino,alkylthio, substituted alkylthio, substituted sulfonyl, substitutedsulfinyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

n is an integer from 0 to 3;

or their tautomers and/or a pharmaceutically acceptable salt thereof,

with the proviso that A is not 1,3-thiazol-2-yl.

In particular embodiments, the heteroaryl group is a 5- or 6-memberedheteroaryl group.

In some embodiments, there are provided compounds of general Formula II:

wherein:

T and W independently are selected from the group consisting of N, NR³,S, S(O), S(O)₂, O, and CR³ and U is selected from the group consistingof N, NR³, S, S(O), S(O)₂, and O with the proviso that no more than oneof T, U, and W are S, S(O), S(O)₂, and O;

R¹ and R² independently are selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, substitutedamino, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino,carboxyl, carboxyl ester, cyano, halo, hydroxyl, acyl, nitro, mercapto,alkylthio, substituted alkylthio, substituted sulfonyl, substitutedsulfonyloxy, substituted sulfinyl, and aminocarbonyl, or R¹ and R² jointogether to form a ring selected from the group consisting of C₅-C₇cycloalkyl, substituted C₅-C₇ cycloalkyl, C₅-C₇ heterocycloalkyl,substituted C₅-C₇ heterocycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl;

R³ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, halo, amino, substituted amino,alkylthio, substituted alkylthio, substituted sulfonyl, substitutedsulfinyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, substitutedamino, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino,carboxyl, carboxyl ester, cyano, halo, hydroxyl, acyl, nitro, mercapto,alkylthio, substituted alkylthio, substituted sulfonyl, substitutedsulfonyloxy, substituted sulfinyl, and aminocarbonyl, or R⁴ and R⁵ jointogether to form a ring selected from the group consisting of C₅-C₇cycloalkyl, substituted C₅-C₇ cycloalkyl, C₅-C₇ heterocycloalkyl,substituted C₅-C₇ heterocycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl; and

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl; substituted aryl, heteroaryl and substituted heteroaryl;

or their tautomers and/or a pharmaceutically acceptable salt thereof.

In some embodiments, one or both of R¹ and R² in Formula II arehydrogen, nitro, or methoxy, respectively.

In some embodiments, one or both of R⁴ and R⁵ in Formula II arehydrogen, methyl, or methoxy, respectively.

In some embodiments, the group

represents pyrazole, thiazole, isoxazole, thiadiazole, or triazole.

In some preferred embodiments, the compounds of the present inventionare represented by Formulas IIa through IIg:

In Formulas IIa through IIg, R¹, R², R⁴ and R⁵ are independentlyhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, substitutedamino, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino,carboxyl, carboxyl ester, cyano, halo, hydroxyl, acyl, nitro, mercapto,alkylthio, substituted alkylthio, substituted sulfonyl, substitutedsulfonyloxy, substituted sulfinyl, and aminocarbonyl, or R¹ and R² jointogether to form a ring, and/or R⁴ and R⁵ join together to form a ringwhere the ring is selected from the group consisting of C₅-C₇cycloalkyl, substituted C₅-C₇ cycloalkyl, C₅-C₇ heterocycloalkyl,substituted C₅-C₇ heterocycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl;

In Formulas IIa through IIg, X, X¹, X², X³, X⁵, X⁶, X⁷, and Zindependently represent O, S, NH, or NR³ where R³ is as defined herein.In some preferred embodiments, X, X¹, X², X³, X⁵, X⁶, X⁷, and Zindependently represent O, S, NH, or NR⁹ where R⁹ is alkyl orsubstituted alkyl.

In one particular embodiment, there are provided compounds of FormulaIIa or its tautomer and/or a pharmaceutically acceptable salt thereof:

wherein X is S or NR⁹ where R⁹ is alkyl or substituted alkyl; and R¹,R², R⁴, R⁵, and R⁶ are as defined herein.

In one preferred embodiment, X is S. In another preferred embodiment, Xis NCH₃.

In one preferred embodiment, R¹ and R² independently are selected fromthe group consisting of hydrogen, nitro, trifluoromethyl, cyano, andhalo.

In one preferred embodiment, R⁴ and R⁵ independently are selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, andsubstituted alkoxy.

In one preferred embodiment, R⁶ is hydrogen.

In one preferred embodiment, there are provided compounds of Formula IIawherein

X is S;

R¹ and R² independently are selected from the group consisting ofhydrogen, nitro, trifluoromethyl, cyano, and halo;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one particularly preferred embodiment, there are provided compoundsof Formula IIa wherein

X is S;

R¹ and R² independently are hydrogen or nitro;

R⁴ and R⁵ independently are hydrogen, methyl, or methoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one preferred embodiment, there are provided compounds of Formula IIawherein

X is NCH₃;

R¹ and R² independently are selected from the group consisting ofhydrogen, nitro, trifluoromethyl, cyano, and halo;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one particularly preferred embodiment, there are provided compoundsof Formula IIa wherein

X is NCH₃;

R¹ and R² independently are hydrogen;

R⁴ and R⁵ independently are hydrogen, methyl, or methoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In some embodiments, there are provided compounds selected from thegroup consisting of

3,4-dimethoxy-N-[3-phenyl-1,2,4-thiadiazol-5-yl]benzenesulfonamide;

4-methyl-N-[3-phenyl-1,2,4-thiadiazol-5-yl]benzenesulfonamide;

3,4-dimethoxy-N-[3-(3-nitrophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;

4-methyl-N-[3-(3-nitrophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;

3,4-dimethoxy-N-(1-methyl-3-phenyl-1,2,4-triazol-5-yl)benzenesulfonamide;and

4-methyl-N-(1-methyl-3-phenyl-1,2,4-triazol-5-yl)benzenesulfonamide.

In a particular embodiment, there are provided compounds of Formula IIbor its tautomer and/or a pharmaceutically acceptable salt thereof:

wherein X¹ is S or NH; and R¹, R², R⁴, R⁵, and R⁶ are as defined herein.

In one preferred embodiment, X¹ is S. In another preferred embodiment,X¹ is NH.

In one preferred embodiment, R¹ and R² independently are selected fromthe group consisting of hydrogen, nitro, trifluromethyl, cyano, andhalo.

In one preferred embodiment, R⁴ and R⁵ independently are selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, andsubstituted alkoxy.

In one preferred embodiment, R⁶ is hydrogen.

In one preferred embodiment, there are provided compounds of Formula IIbwherein

X¹ is S;

R¹ and R² independently are selected from the group consisting ofhydrogen, nitro, trifluromethyl, cyano, and halo;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one particularly preferred embodiment, there are provided compoundsof Formula IIb wherein

X¹ is S;

R¹ and R² independently are hydrogen or nitro;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, methyl, and methoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one preferred embodiment, there are provided compounds of Formula IIbwherein

X¹ is NH;

R¹ and R² independently are hydrogen, nitro, trifluromethyl, cyano, orhalo;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one particularly preferred embodiment, there are provided compoundsof Formula IIb wherein

X¹ is NH;

R¹, R², and R⁶ independently are hydrogen; and

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, methyl, and methoxy; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In some embodiments, there are provided compounds selected from thegroup consisting of

3,4-dimethoxy-N-[3-(phenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;

4-methyl-N-[3-(phenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;

3,4-dimethoxy-N-[3-(3-nitrophenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;

4-methyl-N-[3-(3-nitrophenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;

3,4-dimethoxy-N-[5-(phenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;

4-methyl-N-[5-(phenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;

3,4-dimethoxy-N-[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;and

4-methyl-N-[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide.

In a particular embodiment, there are provided compounds of Formula IIcor their tautomers and/or a pharmaceutically acceptable salt thereof:

wherein X² is O or NR⁹ where R⁹ is alkyl or substituted alkyl; and R¹,R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In one preferred embodiment, X² is O. In another preferred embodiment,X² is NCH₃.

In one preferred embodiment, R¹ and R² independently are selected fromthe group consisting of hydrogen, nitro, trifluromethyl, cyano, or halo.

In one preferred embodiment, R⁴ and R⁵ independently are selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, andsubstituted alkoxy.

In one preferred embodiment, R⁶ is hydrogen.

In one preferred embodiment, there are provided compounds of Formula IIcwherein

X² is O;

R¹ and R² independently are hydrogen, nitro, trifluromethyl, cyano, orhalo;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one particularly preferred embodiment, there are provided compoundsof Formula IIc wherein

X² is O;

R¹ and R² independently are hydrogen;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, methyl, and methoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one preferred embodiment, there are provided compounds of Formula IIcwherein

X² is NCH₃;

R¹ and R² independently are hydrogen;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one particularly preferred embodiment, there are provided compoundsof Formula IIc wherein

X² is NCH₃;

R¹, R², and R⁶ independently are hydrogen;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, methyl, and methoxy; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one embodiment, there are provided compounds selected from the groupconsisting of

3,4-dimethoxy-N-[3-(phenyl)-isoxazol-5-yl]benzenesulfonamide;

4-methyl-N-[3-(phenyl)-isoxazol-5-yl]benzenesulfonamide;

3,4-dimethoxy-N-[1-methyl-3-phenyl-pyrazol-5-yl]benzenesulfonamide; and

4-methyl-N-[1-methyl-3-phenyl-pyrazol-5-yl]benzenesulfonamide.

In another particular embodiment, there are provided compounds ofFormula IId or its tautomer and/or a pharmaceutically acceptable saltthereof:

wherein X³ is S or NR⁹ where R⁹ is alkyl or substituted alkyl; and R¹,R², R⁴, R⁵, and R⁶ are as defined herein.

In one preferred embodiment, X³ is S. In another preferred embodiment,X³ is NCH₃.

In one preferred embodiment, R¹ and R² independently are selected fromthe group consisting of hydrogen, nitro, trifluoromethyl, cyano, andhalo.

In one preferred embodiment, R⁴ and R⁵ independently are selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, andsubstituted alkoxy.

In one preferred embodiment, R⁶ is hydrogen.

In one preferred embodiment, there are provided compounds of Formula IIdwherein

X³ is S;

R¹ and R² independently are selected from the group consisting ofhydrogen, nitro, trifluoromethyl, cyano, and halo;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In one particularly preferred embodiment, there are provided compoundsof Formula IId wherein

X³ is S;

R¹ and R² independently are hydrogen, nitro or chloro;

R⁴ and R⁵ independently are selected from the group consisting ofhydrogen and methoxy; and

R⁶ is hydrogen; or

its tautomer and/or a pharmaceutically acceptable salt thereof.

In some embodiments, there are provided compounds selected from thegroup consisting of

3,4-dimethoxy-N-[5-(4-chlorophenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide;

3,4-dimethoxy-N-[5-(3-nitrophenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide;and

3,4-dimethoxy-N-[5-(phenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide.

In some embodiments, the compounds of the present invention arerepresented by general Formula III:

X⁴ and Y are independently selected from the group consisting of N andC—R⁸;

Ar¹ and Ar² are independently selected from the group consisting ofaryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R⁷ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, amino, substituted amino, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester,cyano, halo, hydroxyl, acyl, nitro, mercapto, alkylthio, substitutedalkylthio, substituted sulfonyl, substituted sulfonyloxy, substitutedsulfinyl, and aminocarbonyl, or 2 or more R⁷ join to form a ring whenm>1 where the ring is selected from the group consisting of C₅-C₇cycloalkyl, substituted C₅-C₇ cycloalkyl, C₅-C₇ heterocycloalkyl,substituted C₅-C₇ heterocycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl;

m is an integer from 0 to 3; and

R⁸ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, halo, amino, substituted amino, aryl, substituted aryl,heteroaryl, and substituted heteroaryl;

or its tautomer and/or a pharmaceutically acceptable salt thereof.

In one group of preferred embodiments, the compounds of the presentinvention are represented by Formulas IIIa through IIId:

In Formulas IIIc through IIId, R¹, R², R⁴, R₅, and R⁶ are independentlyhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, substitutedamino, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino,carboxyl, carboxyl ester, cyano, halo, hydroxyl, acyl, nitro, mercapto,alkylthio, substituted alkylthio, substituted sulfonyl, substitutedsulfonyloxy, substituted sulfinyl, and aminocarbonyl, or R¹ and R² jointogether to form a ring, and/or R⁴ and R⁵ join together to form a ringwhere the ring is selected from the group consisting of C₅-C₇cycloalkyl, substituted C₅-C₇ cycloalkyl, C₅-C₇ heterocycloalkyl,substituted C₅-C₇ heterocycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl;

In Formulas IIIa and IIIb, X⁹ and X¹⁰ independently are N or CH.

Some preferred embodiments of the compounds of Formula III are asfollowing. In some preferred embodiments, X⁴ and Y independently arenitrogen. In some preferred embodiments, X⁴ is nitrogen and Y is CH. Insome preferred embodiments, X⁴ and Y independently are CH.

In some preferred embodiments of the compounds of Formula III, Ar¹ andAr² independently are aryl or substituted aryl. In some particularlypreferred embodiments, Ar¹ is substituted aryl where the substitution ishydrogen, alkyl, or alkoxy. In some particularly preferred embodiments,Ar² is substituted aryl where the substitution is hydrogen, alkyl, oralkoxy.

In some preferred embodiments of the compounds of Formula III, R⁶ ishydrogen. In some preferred embodiments, R⁷ is hydrogen. In somepreferred embodiments, R⁸ is hydrogen.

In some embodiments, there are provided compounds selected from thegroup consisting of

potassium 3,4-dimethoxy-N-[biphenyl-3-yl]benzenesulfonamide;

3,4-dimethoxy-N-[5-(4-methoxyphenyl)-pyrimidin-2-yl]benzenesulfonamide;

4-methyl-N-[5-(4-methoxyphenyl)-pyrimidin-2-yl]benzenesulfonamide;

3,4-dimethoxy-N-[5-(phenyl)-pyridin-2-yl]benzenesulfonamide;

4-methyl-N-[5-(phenyl)-pyridin-2-yl]benzenesulfonamide; and

3,4-dimethoxy-N-[(1,1′-biphenyl)-4-yl]benzenesulfonamide.

The following Table 1 provides exemplary compounds according to someembodiments of the present invention.

TABLE 1 Compound Structure Compound Name

3,4-dimcthoxy-N-[3-(phcnyl)-1,2,4- thiadiazol-5-yl]benzenesulfonamide

4-methyl-N-[3-(phenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

3,4-dimethoxy-N-[3-(3-nitrophenyl)-1,2,4-thiadiazole-5-yl]benzenesulfonamide

4-methyl-N-[3-(3-nitrophenyl)-l,2,4- thiadiazole-5-yl]benzenesulfonamide

3,4-dimethoxy-N-[5-(phenyl)-1,3,4- thiadiazol-2-yl]benzenesulfonamide

4-methyl-N-[5-(phenyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide

3,4-dimethoxy-N-[5-(3-nitrophenyl)-1,3,4-thiadiazole-2-yl]benzenesulfonamide

4-methyl-N-[5-(3-nitrophenyl)-l,3,4- thiadiazole-2-yl]benzenesulfonamide

3,4-dimethoxy-N-[3-(phenyl)-1,2,4- triazole-5-yl]benzenesulfonamide

4-methyl-N-[3-(phenyl)-1,2,4-triazole-5- yl]benzenesulfonamide

3,4-Dimethoxy-N-[5-(3-nitrophenyl)-l,2,4-triazol-3-yl]benzenesulfonamide

4-Methyl-N-[5-(3-nitrophenyl)-1,2,4- triazol-3-yl]benzenesulfonamide

3,4-dimethoxy-N-[3-(phenyl)-isoxazol-5- yl]benzenesulfonamide

4-methyl-N-[3-(phenyl)-isoxazol-5- yl]benzenesulfonamide

3,4-dimethoxy-N-[1-methyl-3-phenyl-pyrazole-5-yl]benzenesulfonamidc

4-methyl-N-[1-methyl-3-phenyl-pyrazole- 5-yl]benzenesulfonamide

3,4-dimethoxy-N-(1-methyl-3-phenyl-l,2,4-triazol-5-yl)benzenesulfonamide

4-methyl-N-(1-methyl-3-phenyl-1,2,4- triazol-5-yl)benzenesulfonamide

3,4-dimethoxy-N-[5-(4-chlorophenyl)-l,2,4-thiadiazolc-3-yl]benzenesulfonamide

3,4-dimethoxy-N-[5-(3-nitrophenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide

3,4-dimethoxy-N-[5-(phenyl)-1,2,4- thiadiazole-3-yl]benzenesulfonamide

Potassium 3,4-dimethoxy-N-[biphenyl-3- yl]benzenesulfonamide

3,4-dimethoxy-N-[5-(4-methoxyphenyl)- pyrimidine-2-yl]benzenesulfonamide

4-methyl-N-[5-(4-methoxyphenyl)- pyrimidine-2-yl]benzenesulfonamide

3,4-dimethoxy-N-[5-(phenyl)-pyridine-2- yl]benzenesulfonamide

4-methyl-N-[5-(phenyl)-pyridine-2- yl]benzenesulfonamide

3,4-dimethoxy-N-[biphenyl-4- yl]benzenesulfonamide

3. Compositions and Methods of the Invention

This invention provides compounds and composition which are useful intherapeutic applications. In particular, the compounds represented byFormula I, II, IIa, IIb, IIc, IId, IIe, IIf, IIg, III, IIIa, IIIb, IIIc,or IIId and their salts and/or tautomers can effectively act asinhibitors of kynurenine-3-monooxygenase (KMO) and inhibit the KMOactivities in the brain. In one aspect of the invention, the inventionprovides pharmaceutical compositions comprising one or more compounds ofFormula I, II, IIa, IIb, IIc, IId, IIe, IIf, IIg, III, IIIa, IIIb, IIIc,or IIId and a pharmaceutically acceptable excipient.

In one of its method aspects, this invention is directed to a method forinhibiting activity of kynurenine-3-monooxygenase activity which methodcomprises contacting cells (including neurons/microglia/invadingmacrophages) with an effective amount of one or more compounds ofFormula I, II, IIa, IIb, IIc, IId, IIe, IIf, IIg, III, IIIa, IIIb, IIIc,or IIId. The compounds of the invention are useful in inhibiting theactivity of kynurenine-3-monooxygenase activity in the CNS as well as inperipheral immune cells. The compounds are also useful for treatingperipheral infections or immune dysfunction.

In another of its method aspects, this invention is directed to a methodfor treating a disease mediated at least in part bykynurenine-3-monooxygenase which method comprises administering to apatient an effective amount of one or more compounds of Formula I or apharmaceutical composition comprising a pharmaceutically acceptableexcipient and one or more compounds of Formula I, II, IIa, IIb, IIc,IId, IIe, IIf, IIg, III, IIIa, IIIb, IIIc, or IIId.

Diseases mediated at least in part by kynurenine-3-monooxygenase includethose selected from the group consisting of Huntington's disease andother polyglutamine disorders such as spinocerebellar ataxias,Alzheimer's disease, Parkinson's disease, high-pressure neurologicalsyndrome, dystonia, olivopontocerebellar atrophy, amyotrophic lateralsclerosis, multiple sclerosis, epilepsy, consequences of stroke,cerebral ischemia, hypoxia, multi-infarct dementia, consequences ofcerebral trauma or damage, damage to the spinal cord, AIDS-dementiacomplex, viral or bacterial meningitis, general central nervous system(CNS) infections such as viral, bacterial or parasites, for example,poliomyelitis, Lyme disease (Borrelia burgdorferi infection) andmalaria, cancers with cerebral localization, Tourette's syndrome,hepatic encephalopathy, systemic lupus, analgesia and opiate withdrawalsymptoms, feeding behaviour, schizophrenia, chronic anxiety, depressivedisorders, disorders of the developing or aged brain, diseases ofaddiction, diabetes, and complications thereof. The compounds of thisinvention may also influence synaptogenesis after brain injury. Thecompounds also may influence memory. The diseases of addiction refer toaddictive diseases which adversely affect or alter the neuronal functionincluding by way of example, drug addiction such as alcoholism, nicotineaddiction, illicit drug addiction (e.g., heroine, cocaine, marijuana,etc.).

The compounds are useful in the diagnosis and treatment of a variety ofhuman diseases including neurodegenerative and neurological disorders,consequences of stroke and/or cerebral ischaemia, hypoxia, multi-infarctdementia, consequences of trauma and damages to the cerebrum or spinalcord, autoimmune disease, and psychiatric illness. For example, thecompounds of the present invention are particularly useful in treatingneurodegenerative disorders such as Huntington's disease and otherpolyglutamine disorders such as spinocerebellar ataxias, Alzheimer'sdisease, Parkinson's disease, high-pressure neurological syndrome,dystonia, olivopontocerebellar atrophy, amyotrophic lateral sclerosis,multiple sclerosis, epilepsy, consequences of stroke, cerebral ischemia,hypoxia, multi-infarct dementia, consequences of cerebral trauma ordamage, damage to the spinal cord, AIDS-dementia complex, viral orbacterial meningitis, general central nervous system (CNS) infectionssuch as viral, bacterial or parasites, for example, poliomyelitis, Lymedisease (Borrelia burgdorferi infection) and malaria, cancers withcerebral localization, Tourette's syndrome, hepatic encephalopathy,systemic lupus, analgesia and opiate withdrawal symptoms, feedingbehaviour, schizophrenia, chronic anxiety, depressive disorders,disorders of the developing or aged brain, diseases of addiction,diabetes, and complications thereof. The compounds of this invention mayalso influence synaptogenesis after brain injury. The compounds also mayinfluence memory.

4. General Synthetic Methods

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and P. G. M. Wuts, Protecting Groups inOrganic Synthesis, Third Edition, Wiley, New York, 1999, and referencescited therein.

If the compounds of this invention contain one or more chiral centers,such compounds can be prepared or isolated as pure stereoisomers, i.e.,as individual enantiomers or diastereomers, or as stereoisomer-enrichedmixtures. All such stereoisomers (and enriched mixtures) are includedwithin the scope of this invention, unless otherwise indicated. Purestereoisomers (or enriched mixtures) may be prepared using, for example,optically active starting materials or stereoselective reagentswell-known in the art. Alternatively, racemic mixtures of such compoundscan be separated using, for example, chiral column chromatography,chiral resolving agents and the like.

Synthesis of Compounds of the Invention

In one general embodiment, the method involves reacting an appropriatebenzenesulfonyl halide with an appropriate amine.

For example, the compounds of general Formula I can be preparedaccording to Scheme 1:

In Scheme 1, compound 1 is combined with an equimolar amount andpreferably an excess of compound 2 under coupling conditions to providefor compound 3. Specifically, this reaction is typically conducted byreacting amino compound 1 with at least one equivalent, preferably about1.1 to about 2 equivalents, of sulfonyl halide (e.g., chloride),compound 2, in an inert diluent such as dichloromethane and the like.Generally, the reaction is conducted at a temperature ranging from about−70° C. to about 40° C. for about 1 to about 24 h. Preferably, thisreaction is conducted in the presence of a suitable base to scavenge theacid generated during the reaction. Suitable bases include, by way ofexample, tertiary amines, such as triethylamine, diisopropylethylamine,N-methylmorpholine and the like. Alternatively, the reaction can beconducted under Schotten-Baumann-type conditions using aqueous alkali,such as sodium hydroxide and the like, as the base. Alternatively,compound 1 can be reacted with compound 2 in pyridine solution wherepyridine acts both as a base and as a solvent. Upon completion of thereaction, the resulting N-sulfonyl compound 3 is recovered byconventional methods including neutralization, extraction,precipitation, chromatography, filtration, and the like.

The sulfonyl halides of compound 2 are either known compounds orcompounds that can be prepared from known compounds by conventionalsynthetic procedures. Such compounds are typically prepared from thecorresponding sulfonic acid, i.e., from compounds of the formula Ar²SO₃Hwhere Ar² is as defined herein, using phosphorus trihalide andphosphorus pentahalide. This reaction is generally conducted bycontacting the sulfonic acid with about 2 to 5 molar equivalents ofphosphorus trihalide and phosphorus pentahalide, either neat or in aninert solvent, such as dichloromethane, at temperature in the range ofabout 0° C. to about 80° C. for about 1 to about 48 h to afford thesulfonyl halide. Alternatively, the sulfonyl halides can be preparedfrom the corresponding thiol compound, i.e., from compounds of theformula Ar²—SH where Ar² is as defined herein, by treating the thiolwith chlorine (Cl₂) and water under conventional reaction conditions.

Examples of sulfonyl chlorides suitable for use in this inventioninclude, but are not limited to, methanesulfonyl chloride,2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonylchloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonylchloride, p-toluenesulfonyl chloride, α-toluenesulfonyl chloride,4-acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride,4-tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride,2-carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride,3,4-dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonylchloride, 3,4-dimethoxybenzenesulfonyl chloride,3,5-ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonylchloride, 4-methoxybenzenesulfonyl chloride,2-methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulfonylchloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonylchloride, 4-trifluoromethylbenzenesulfonyl chloride,4-trifluoromethoxybenzenesulfonyl chloride,2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonylchloride, 2-thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonylchloride, 2,5-dichloro-4-thiophenesulfonyl chloride, 2-thiazolesulfonylchloride, 2-methyl-4-thiazolesulfonyl chloride,1-methyl-4-imidazolesulfonyl chloride, 1-methyl-4-pyrazolesulfonylchloride, 5-chloro-1,3-dimethyl-4-pyrazolesulfonyl chloride,3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride and the like.If desired, a sulfonyl fluoride, sulfonyl bromide or sulfonic acidanhydride may be used in place of the sulfonyl chloride in the abovereaction to form the N-sulfonyl compound 3.

Amino compound 1 is prepared from known compounds or can be prepared inanalogy to known methods. For example, the appropriate aryl-substitutedamino-thiazole can be prepared according to Scheme 2:

This reaction is typically conducted by adding equimolar amounts ofcompound 4 and 5 in a polar solvent, such as ethanol or isopropanol, ata temperature ranging from about 40° C. to about 100° C. The product canbe recovered by conventional methods such as crystallization.

Other known heterarylamines can be prepared in a manner similar to theabove and are illustrated in the examples below. Alternatively,heteroarylamines can be prepared using methodology well known in the artsuch as Suzuki coupling of an aromatic or heteroaromatic halide with anaromatic or heteroaromatic boron derivative using techniques well knownin the art. Typically some of such heteroarylamines can be commerciallyavailable from vendors such as Aldrich Chemical Company including, forexample, 3-amino-5-phenylpyrazole, 2-amino-5-phenyl-1,3,4-thiadiazole,2-amino-4-(p-tolyl)-thiazole, 2-amino-4-(4-bromophenyl)-thiazole,2-amino-4-(4-chlorophenyl)-thiazole, and the like.

The compounds of the general Formula III can be prepared according toScheme 3:

Scheme 3 proceeds substantially as described above for Scheme 1.

Heteroarylamines or arylamines represented by compound 7 can be preparedin a manner similar to the above and are illustrated in the examplesbelow. Alternatively, heteroarylamines and arylamines can be preparedusing methodology well known in the art such as Suzuki coupling of anaromatic or heteroaromatic halide with an aromatic or heteroaromaticboron derivative using techniques well known in the art. Typically someof these 6 membered aryl and heteroarylamines can be commerciallyavailable from vendors such as Aldrich Chemical Company including, forexample, 2-(2-aminophenyl)indole, 2-aminobiphenyl, 4-aminobiphenyl, andthe like.

The compounds of the general Formula IIb such as 1,2,4-triazolecompounds can be prepared according to Scheme 4:

This reaction is typically conducted by adding an equimolar amounts of3-nitrobenzoyl chloride 10 and thiosemicarbazide 11 to phosphorusoxychloride and refluxing the reaction mixture. The product can berecovered by conventional methods such as filtration where the reactionresults in a mixture of aminotriazole 12 and thiadiazole 13. The mixturecan be used as such and is stirred at room temperature with3,4-dimethoxybenzenesulfonyl chloride 14. The product can be recoveredby conventional methods such as filtration and/or crystallization.

Such derivations are contemplated to allow for active metabolites to beformed in the brain rather than in the peripheral circulation andinhibits KMO activity in the brain upon metabolic activation as anirreversible enzyme inhibitor.

5. Use of Compounds of the Invention

The compounds in accordance with the present invention have highactivities as inhibitors of kynurenine-3-monooxygenase.

The KMO inhibiting activities of the compounds of the present inventionwere evaluated using standard methods. See Erickson et al., ARadiometric Assay for Kynurenine 3-Hydroxylase Based on the Release of³H₂O During Hydroxylation of L-[3,5-³H]-Kynurenine, Anal. Biochem. 1992,205, 257-262, the disclosure of which is hereby incorporated byreference.

Table 2 shows IC₅₀ values or percent inhibition for some of thecompounds of this invention. The IC₅₀ value is the half maximalinhibitory concentration and represents the concentration of aninhibitor that is required for 50% inhibition of an enzyme activity andthe percent inhibition measures the amount of enzyme activity inhibitedat a given concentration of compound. If the administered compound is aprodrug then the prodrug may not inhibit KMO until it has metabolizedappropriately.

TABLE 2 % inhibition Compound^(#) at 10 uM A1  73.61 A2  77.9 A5  60.03A6  71.59 A13 17.82 A14 30.74 A15 * A16 * A9  * A10 * A19 68.6 A22 19.57A23 17.5 A24 * A25 24.8 A26 * A27 * ^(#)The compounds in this table havebeen identified in Table 1 herein *The compounds are contemplated tohave inhibition activity at higher concentrations

6. Administration and Pharmaceutical Composition

The present invention provides novel compounds possessing KMO inhibitionactivity and, accordingly, are useful in treating disorders mediated by(or at least in part by) the presence of 3-hydroxykynurenine and/orquinolinic acid. Such diseases include, for example, Huntington'sdisease and other polyglutamine disorders such as spinocerebellarataxias, Alzheimer's disease, Parkinson's disease, high-pressureneurological syndrome, dystonia, olivopontocerebellar atrophy,amyotrophic lateral sclerosis, multiple sclerosis, epilepsy,consequences of stroke, cerebral ischemia, hypoxia, multi-infarctdementia, consequences of cerebral trauma or damage, damage to thespinal cord, AIDS-dementia complex, viral or bacterial meningitis,general central nervous system (CNS) infections such as viral, bacterialor parasites, for example, poliomyelitis, Lyme disease (Borreliaburgdorferi infection) and malaria, cancers with cerebral localization,Tourette's syndrome, hepatic encephalopathy, systemic lupus, analgesiaand opiate withdrawal symptoms, feeding behaviour, schizophrenia,chronic anxiety, depressive disorders, disorders of the developing oraged brain, diabetes, and complications thereof.

In general, the compounds of this invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the compound of this invention, i.e., the active ingredient,will depend upon numerous factors such as the severity of the disease tobe treated, the age and relative health of the subject, the potency ofthe compound used, the route and form of administration, and otherfactors well know to the skilled artisan. The drug can be administeredat least once a day, preferably once or twice a day.

An effective amount of such agents can readily be determined by routineexperimentation, as can the most effective and convenient route ofadministration, and the most appropriate formulation. Variousformulations and drug delivery systems are available in the art. See,e.g., Gennaro, A. R., ed. (1995) Remington's Pharmaceutical Sciences,18^(th) ed., Mack Publishing Co.

A therapeutically effective dose can be estimated initially using avariety of techniques well-known in the art. Initial doses used inanimal studies may be based on effective concentrations established incell culture assays. Dosage ranges appropriate for human subjects can bedetermined, for example, using data obtained from animal studies andcell culture assays.

An effective amount or a therapeutically effective amount or dose of anagent, e.g., a compound of the invention, refers to that amount of theagent or compound that results in amelioration of symptoms or aprolongation of survival in a subject. Toxicity and therapeutic efficacyof such molecules can be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., bydetermining the LD50 (the dose lethal to 50% of the population) and theED50 (the dose therapeutically effective in 50% of the population). Thedose ratio of toxic to therapeutic effects is the therapeutic index,which can be expressed as the ratio LD50/ED50. Agents that exhibit hightherapeutic indices are preferred.

The effective amount or therapeutically effective amount is the amountof the compound or pharmaceutical composition that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. Dosages particularly fall within a range of circulatingconcentrations that includes the ED50 with little or no toxicity.Dosages may vary within this range depending upon the dosage formemployed and/or the route of administration utilized. The exactformulation, route of administration, dosage, and dosage interval shouldbe chosen according to methods known in the art, in view of thespecifics of a subject's condition.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety that are sufficient to achieve thedesired effects; i.e., the minimal effective concentration (MEC). TheMEC will vary for each compound but can be estimated from, for example,in vitro data and animal experiments. Dosages necessary to achieve theMEC will depend on individual characteristics and route ofadministration. In cases of local administration or selective uptake,the effective local concentration of the drug may not be related toplasma concentration.

The amount of agent or composition administered may be dependent on avariety of factors, including the sex, age, and weight of the subjectbeing treated, the severity of the affliction, the manner ofadministration, and the judgment of the prescribing physician.

This invention is not limited to any particular composition orpharmaceutical carrier, as such may vary. In general, compounds of thisinvention will be administered as pharmaceutical compositions by any oneof the following routes: oral, systemic (e.g., transdermal, intranasalor by suppository), or parenteral (e.g., intramuscular, intravenous orsubcutaneous) administration. The preferred manner of administration isoral using a convenient daily dosage regimen that can be adjustedaccording to the degree of affliction. Compositions can take the form oftablets, pills, capsules, semisolids, powders, sustained releaseformulations, solutions, suspensions, elixirs, aerosols, or any otherappropriate compositions. Another preferred manner for administeringcompounds of this invention is inhalation.

The choice of formulation depends on various factors such as the mode ofdrug administration and bioavailability of the drug substance. Fordelivery via inhalation the compound can be formulated as liquidsolution, suspensions, aerosol propellants or dry powder and loaded intoa suitable dispenser for administration. There are several types ofpharmaceutical inhalation devices-nebulizer inhalers, metered doseinhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices producea stream of high velocity air that causes the therapeutic agents (whichare formulated in a liquid form) to spray as a mist that is carried intothe patient's respiratory tract. MDI's typically are formulationpackaged with a compressed gas. Upon actuation, the device discharges ameasured amount of therapeutic agent by compressed gas, thus affording areliable method of administering a set amount of agent. DPI dispensestherapeutic agents in the form of a free flowing powder that can bedispersed in the patient's inspiratory air-stream during breathing bythe device. In order to achieve a free flowing powder, the therapeuticagent is formulated with an excipient such as lactose. A measured amountof the therapeutic agent is stored in a capsule form and is dispensedwith each actuation.

Pharmaceutical dosage forms of a compound of the present invention maybe manufactured by any of the methods well-known in the art, such as,for example, by conventional mixing, sieving, dissolving, melting,granulating, dragee-making, tabletting, suspending, extruding,spray-drying, levigating, emulsifying, (nano/micro-) encapsulating,entrapping, or lyophilization processes. As noted above, thecompositions of the present invention can include one or morephysiologically acceptable inactive ingredients that facilitateprocessing of active molecules into preparations for pharmaceutical use.

Recently, pharmaceutical formulations have been developed especially fordrugs that show poor bioavailability based upon the principle thatbioavailability can be increased by increasing the surface area i.e.,decreasing particle size. For example, U.S. Pat. No. 4,107,288 describesa pharmaceutical formulation having particles in the size range from 10to 1,000 nm in which the active material is supported on a crosslinkedmatrix of macromolecules. U.S. Pat. No. 5,145,684 describes theproduction of a pharmaceutical formulation in which the drug substanceis pulverized to nanoparticles (average particle size of 400 nm) in thepresence of a surface modifier and then dispersed in a liquid medium togive a pharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of in general, a compound of the presentinvention in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the claimedcompounds. Such excipient may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc. Other suitable pharmaceutical excipients and theirformulations are described in Remington's Pharmaceutical Sciences,edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

The present compositions may, if desired, be presented in a pack ordispenser device containing one or more unit dosage forms containing theactive ingredient. Such a pack or device may, for example, comprisemetal or plastic foil, such as a blister pack, or glass, and rubberstoppers such as in vials. The pack or dispenser device may beaccompanied by instructions for administration. Compositions comprisinga compound of the invention formulated in a compatible pharmaceuticalcarrier may also be prepared, placed in an appropriate container, andlabeled for treatment of an indicated condition.

The amount of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt% of a compound of the present invention based on the total formulation,with the balance being one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 1-80 wt %.Representative pharmaceutical formulations are described below.

FORMULATION EXAMPLES

The following are representative pharmaceutical formulations containinga compound of formula I.

Formulation Example 1 Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Quantity per Ingredient tablet, mg compound of this invention 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Formulation Example 2 Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Quantity per Ingredient capsule, mg compound of this invention 200lactose, spray-dried 148 magnesium stearate 2

Formulation Example 3 Suspension Formulation

The following ingredients are mixed to form a suspension for oraladministration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 gsodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 ggranulated sugar 25.0 g sorbitol (70% solution) 13.00 g Veegum K(Vanderbilt Co.) 1.0 g flavoring 0.035 mL colorings 0.5 mg distilledwater q.s. to 100 mL

Formulation Example 4 Injectable Formulation

The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention 0.2 mg-20 mg sodium acetatebuffer solution, 0.4 M 2.0 mL HC1 (1N) or NaOH (1N) q.s. to suitable pHwater (distilled, sterile) q.s. to 20 mL

Formulation Example 5 Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing the compoundof the invention with Witepsol® H-15 (triglycerides of saturatedvegetable fatty acid; Riches-Nelson, Inc., New York), and has thefollowing composition:

Ingredient Amount Compound of the invention 500 mg Witepsol ® H-15balance

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

bd=broad doublet

bm=broad multiplet

bs=broad singlet

CH₂Cl₂=dichloromethane

d=doublet

dd=doublet of doublets

DMF=dimethylformamide

DMSO=dimethyl sulfoxide

EtOAc=ethyl acetate

EtOH=ethanol

g=gram

h=hour/s

HCl=hydrochloric acid

HOAc=acetic acid

Hz=hertz

KOH=potassium hydroxide

m=multiplet

M=molar

MeOH=methanol

mg=milligrams

mL=milliliters

mmol=millimols

mp=melting point

MS=mass spectroscopy

m/z=mass to charge ratio

NMR=nuclear magnetic resonance

NaOH=sodium hydroxide

Na₂SO₄=sodium sulfate

s=singlet

t=triplet

TLC=thin layer chromatography

UV=ultraviolet

wt %=weight percent

Example 13,4-Dimethoxy-N-[3-(phenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

3-Phenyl-1,2,4-thiadiazol-5-amine (326 mg, 1.84 mmol) was dissolved indry pyridine (10 mL). Then 3,4-dimethoxybenzenesulfonyl chloride (529mg, 2.23 mmol) was added. The solution was stirred at room temperatureunder Argon. After 46 h, the pyridine was removed in vacuo and flashedoff with toluene. The residue was partitioned between EtOAc and 1M NaOH.The organic phase was washed with 1M NaOH until no turbidity wasobserved on rectification of a small sample. The alkaline phase was madeacidic (˜pH 3) with 1M HCl and extracted with EtOAc. After drying overNa₂SO₄, the solvent was removed in vacuo to give a solid (100 mg) whichwas crystallized from EtOAc. Yield was 29.3 mg; mp 170-171° C.

¹H NMR (DMSO d₆) δ 3.80 (s, 3H), 3.81 (s, 3H), 7.11 (d, J=8.4 Hz, 1H),7.30 (d, J=2.0 Hz, 1H), 7.46 (dd, J=2.0, 8.4 Hz, 1H), 7.49-7.57 (m, 3H),7.98 (m, 2H).

Example 24-Methyl-N-[3-(phenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

3-Phenyl-1,2,4-thiadiazol-5-amine or 3-phenyl-5-amino-1,2,4-thiadiazole(326 mg, 1.84 mmol) was dissolved in dry pyridine (10 mL) and4-methylbenzenesulfonyl chloride (427 mg) was added and the solution wasstirred at room temperature for 48 h. Using the same procedure asExample 3 except that the initial partition was between 1 M NaOH andCH₂Cl₂. The pyridine was removed in vacuo and flashed off with toluene.The residue was partitioned between CH₂Cl₂ and 1M NaOH. The organicphase was washed with 1 M NaOH until no turbidity was observed onrectification of a small sample. The alkaline phase was made acidic (˜pH3) with 1M HCl and extracted with EtOAc. After drying over Na₂SO₄, thesolvent was removed in vacuo. The crude product was crystallized fromEtOH. A first crop of white needles 57.4 g was obtained, mp 217-218° C.A second crop (18.3 mg) of slightly pink product was obtained from 70%ethanol, mp 215-216° C.

¹H NMR (DMSO d₆) δ 2.36 (s, 3H), 7.38 (d, J=8.2 Hz, 2H), 7.50-7.57 (m,3H), 7.75 (d, J=8.2 Hz, 2H), 7.98 (bd, 2H).

Example 3 Potassium 3,4-dimethoxy-N-[biphenyl-3-yl]benzenesulfonamide

To a solution of biphenyl-3-amine (338 mg, 2 mmol) in dry pyridine (10mL) was added 3,4-dimethoxybenzenesulfonyl chloride (529 mg, 2.23 mmol).The mixture was left at room temperature for 69 h. After the pyridinewas removed in vacuo, the residue was partitioned between CH₂Cl₂ andNaOH. A very viscous oil (0.664 g, 1.8 mmol) was obtained and thendissolved in 10 mL of EtOH and a solution of KOH in EtOH (7.3 mL of asolution containing 322 mg of 85% KOH in 20 mL of EtOH). The solvent wasremoved in vacuo leaving a viscous oil. This was taken up in EtOH anddiluted with an equal amount of toluene. A solid crystallized onstanding. It was collected by filtration, washed with toluene and driedin vacuo to give 600 mg of a white solid, mp 262-264° C.

Example 43,4-Dimethoxy-N-[3-(phenyl)-1,2,4-triazol-5-yl]benzenesulfonamide

To a solution of 5-phenyl-4H-1,2,4-triazol-3-amine (354 mg, 2 mmol) indry pyridine (10 mL) was added 3,4-dimethoxybenzenesulfonyl chloride(529 mg, 2.23 mmol). The solution was stirred at room temperature underArgon. After 48 h, the pyridine was removed in vacuo and flashed offwith toluene. The residue was partitioned between CH₂Cl₂ and 1M NaOH.The organic phase was washed with 1M NaOH until no turbidity wasobserved on rectification of a small sample. The alkaline phase was madeacidic (˜pH 3) with 1M HCl and extracted with CH₂Cl₂. After drying overNa₂SO₄, the solvent was removed in vacuo to give 0.47 g crude product.The crude product was dissolved in hot HOAc (22 mL), diluted with water(9 mL) and seeded. The product was collected by filtration, washed withwater, then EtOH and dried in vacuo to give 361 mg of a granular whitesolid, mp 245-246° C.

¹H NMR (DMSO d₆) δ 3.79 (s, 6H), 7.08 (bm, 1H), 7.43-7.48 (bm, 6H), 7.84(bs, 2H), 10.91 (bs, 1H).

Example 5 4-Methyl-N[3-(phenyl)-1,2,4-triazol-5-yl]benzenesulfonamide

To a solution of 5-phenyl-4H-1,2,4-triazol-3-amine (354 mg, 2 mmol) indry pyridine (10 mL) was added 4-methylbenzenesulfonyl chloride (427 mg,2.24 mmol). The solution was stirred at room temperature under Argon.After 48 h, the pyridine was removed in vacuo and flashed off withtoluene. The residue was partitioned between CH₂Cl₂ and 1M NaOH. Theorganic phase was washed with 1M NaOH until no turbidity was observed onrectification of a small sample. The alkaline phase was made acidic (˜pH3) with 1M HCl and extracted with CH₂Cl₂. After drying over Na₂SO₄, thesolvent was removed in vacuo to give 0.41 g crude product. The crudeproduct was dissolved hot EtOAc (16 mL), diluted with hexane (16 mL),and seeded to give fine white needles (304 mg) with mp 220-221° C.

¹H NMR (DMSO d₆) δ 2.34 (s, 3H), 7.31-7.36 (bm, 3H), 7.48 (bs, 3H),7.77-7.84 (bm, 4H), 11.04 (bs, 1H).

Example 6 3,4-Dimethoxy-N[3-(phenyl)-isoxazol-5-yl]benzenesulfonamide

To a solution of 3-phenylisoxazol-5-amine (320 mg, 2 mmol) in 10 mL ofdry pyridine was added 3,4-dimethoxybenzenesulfonyl chloride (529 mg,2.23 mmol). The solution was stirred at room temperature under Argon.After 24 h, the pyridine was removed in vacuo and flashed off withtoluene. The residue was partitioned between CH₂Cl₂ and 1M NaOH. Theorganic phase was washed with 1M NaOH until no turbidity was observed onrectification of a small sample. The alkaline phase was made acidic (˜pH3) with 1M HCl and extracted with CH₂Cl₂. After drying over Na₂SO₄, thesolvent was removed in vacuo. The crude product was crystallized fromEtOH to give 88 mg of a white solid. The product showed a single spot onTLC (SiO₂, 1% MeOH in CH₂Cl₂, UV), less polar than starting materialwith mp 151-152° C.

Example 7 4-Methyl-N[3-(phenyl)-isoxazol-5-yl]benzenesulfonamide

To a solution of 3-phenylisoxazol-5-amine (320 mg) in 10 mL of drypyridine was added 4-methylbenzenesulfonyl chloride (427 mg, 2240 mmol).The solution was stirred at room temperature under Argon. After 25 h,the pyridine was removed in vacuo and flashed off with toluene. Theresidue was partitioned between CH₂Cl₂ and water. The CH₂Cl₂ phase wasdried over Na₂SO₄ and the solvent was removed in vacuo. The oily residuepartially crystallized on titration with EtOH. The product wascrystallized from EtOH to give 61 mg of pink needles. The product was asingle spot by TLC (1% MeOH in CH₂Cl₂, SiO₂, UV) less polar thanstarting material with mp 191-193° C.

Example 83,4-Dimethoxy-N-[5-(4-methoxyphenyl)-pyrimidine-2-yl]benzenesulfonamide

To a solution of 5-(4-methoxyphenyl)pyrimidin-2-amine (302 mg, 1.5 mmol)in 10 mL of dry pyridine was added 3,4-dimethoxybenzenesulfonyl chloride(398 mg, 1.68 mmol). The solution was stirred at room temperature underArgon. After 24 h, the pyridine was removed in vacuo and flashed offwith toluene. The residue was partitioned between EtOAc and 1M HCl.EtOAc phase was washed with water to neutral, dried over Na₂SO₄ andevaporated in vacuo to give 0.20 g of a solid which was taken up in 4 mLof hot HOAc, diluted with 2 mL of water which initiated crystallizationto give 181 mg of product with mp 218-220° C.

¹H NMR (DMSO d₆) δ 3.76-3.83 (m, 9H), 6.99-7.03 (m, 2H), 7.09-7.13 (m,1H), 7.56-7.63 (m, 4H), 8.79, 8.80 (singlets, total 1H), 10.23 (s, 1H).

Example 94-Methyl-N-[5-(4-methoxyphenyl)-pyrimidine-2-yl]benzenesulfonamide

To a solution of 5-(4-methoxyphenyl)pyrimidin-2-amine (302 mg, 1.5 mmol)in 10 mL of dry pyridine was added 4-methylbenzenesulfonyl chloride (320mg, 1.68 mmol). The solution was stirred at room temperature underArgon. After 21 h, the pyridine was removed in vacuo and flashed offwith toluene. The residue was partitioned between CH₂Cl₂ and 1M NaOH.The organic phase was washed with 1M NaOH until no turbidity wasobserved on rectification of a small sample. The alkaline phase was madeacidic (˜pH 3) with 1M HCl and extracted with EtOAc. The crude solidproduct weighed 180 mg. The crude product was taken up in hot HOAc (4mL) and diluted with 2 mL of water to initiate crystallization. Theproduct was collected by filtration, washed with water and EtOH anddried in vacuo to give white needles (147 mg) with mp 220-223° C.

Example 103,4-Dimethoxy-N-[1-methyl-3-phenyl-pyrazol-5-yl]benzenesulfonamide

To a solution of 1-methyl-3-phenyl-pyrazol-5-amine (346 mg, 2 mmol) in10 mL of dry pyridine was added 529 mg (2.23 mmol) of3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at roomtemperature under Argon. After 22 h, the pyridine was removed in vacuoand flashed off with toluene. The crude base soluble material (1M NaOH)weighed 1.1 g. The crude product was taken up in EtOAc and extractedwith 1M NaOH and H₂O alternately. The basic aqueous phase was madeacidic with 1M HCl, extracted with EtOAc, washed with water, dried andevaporated in vacuo to give a cream colored solid (0.70 g) which wastaken up in 5 mL of hot EtOH, diluted with 5 mL of H₂O and seeded togive 473 mg of a solid with mp 163-165° C. after drying in vacuo.

¹H NMR (DMSO d₆) δ 3.59 (s, 3H), 3.75 (s, 3H), 3.83 (s, 3H), 6.19 (s,1H), 7.12 (d, J=8.4 Hz, 1H), 7.24-7.28 (m, 2H), 7.31-7.36 (m, 3H), 7.67(d, J=7.2 Hz, 2H).

¹³C NMR (DMSO d₆) δ 35.331, 55.705, 55.841, 98.365, 109.285, 111.168,124.7, 127.555, 128.595, 130.744, 132.924, 135.938, 148.247, 152.507.

Example 11 4-Methyl-N-[1-methyl-3-phenyl-pyrazol-5-yl]benzenesulfonamide

To a solution of 1-methyl-3-phenyl-pyrazol-5-amine (346 mg, 2 mmol) indry pyridine was (10 mL) added 427 mg (2.24 mmol) of4-methylbenzenesulfonyl chloride. The solution was stirred at roomtemperature under Argon. After 25 h, the pyridine was removed in vacuoand flashed off with toluene, and the residue was partitioned betweenEtOAc and 1M HCl. After washing with water and drying over Na₂SO₄, thesolvent was removed in vacuo to give 0.67 g of a 1M NaOH soluble solid.The product was taken up in 15 mL of EtOAc, diluted with 15 mL of hexaneand seeded to give 0.429 g of a yellow solid which was a single spot onTLC (SiO₂, UV, 5% MeOH in CH₂Cl₂) with mp 206-208° C.

¹H NMR (DMSO d₆) δ 2.37, 2.39 (singlets, total 3H), 3.57, 3.58(singlets, total 3H), 6.15, 6.16 (singlets, total 1H), 7.23-7.42 (m,7H), 7.64-7.66 (m, 2H), 10.38, 10.39 (singlets, total 1H).

Example 123,4-Dimethoxy-N-(1-methyl-3-phenyl-1,2,4-triazol-5-yl)benzenesulfonamide

To a solution of 1-methyl-3-phenyl-1,2,4-triazol-5-amine (320 mg, 2mmol) in 10 mL dry pyridine was added 529 mg (2.23 mmol) of3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at roomtemperature under Argon. After 21 h, the pyridine was removed in vacuoand flashed off with toluene. The salt was partitioned between EtOAc andwater. The EtOAc phase was extracted alternately with 1M NaOH and H₂O.The basic phase was made acid (pH˜3) with 1M HCl and extracted withEtOAc. The organic phase was evaporated in vacuo, toluene was added andwas again evaporated in vacuo to give a white solid. The product wastaken up in hot HOAc (16 mL), diluted with H₂O (10 mL) and seeded togive 143 mg of white needles with mp 279-280° C. after drying in vacuo.

Example 134-Methyl-N-(1-methyl-3-phenyl-1,2,4-triazol-5-yl)benzenesulfonamide

To a solution of 1-methyl-3-phenyl-1,2,4-triazol-5-amine (320 mg, 2mmol) in 10 mL of dry pyridine was added 427 mg of4-methylbenzenesulfonyl chloride (224 mmol). The solution was stirred atroom temperature under Argon. After 23 h, the pyridine was removed invacuo and flashed off with toluene, and the residue was partitionedbetween 1M NaOH and EtOAc. The alkaline phase was made acidic and theflocculent solid was collected by filtration and taken up in acetone.The aqueous phase was extracted with EtOAc, washed with H₂O and driedover Na₂SO₄. The acetone and the EtOAc phases were combined andevaporated in vacuo to give 0.15 g of a white solid which was taken upin hot HOAc (7 mL), diluted with water (4 mL), and seeded to give 80 mgof needles with mp 300-302° C.

Example 14 3,4-Dimethoxy-N[5-(phenyl)-pyridine-2-yl]benzenesulfonamide

To a solution of 5-phenylpyridin-2-amine (340 mg, 2 mmol) in 10 mL ofdry pyridine was added 3,4-dimethoxybenzenesulfonyl chloride (529 mg,2.23 mmol). The solution was stirred at room temperature under Argon.After 19 h, the pyridine was removed in vacuo and flashed off withtoluene, the solid residue was partitioned between EtOAc and 1M NaOH.The alkaline phase was made acidic and the solid was collected byfiltration and dried in vacuo to give 511 mg of a solid. This was takenup in 5 mL of HOAc, diluted with 3 mL of water; crystallization tookplace to give 447 mg of a white crystalline product with mp 202-204° C.

¹H NMR (DMSO d₆) δ 3.79 (s, 6H), 7.08 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.8Hz, 1H), 7.33-7.50 (m, 6H), 7.62 (d, J=8.4 Hz, 1H), 8.01 (bd, J=8.8 Hz,1H), 8.44 (bs, 1H), 11.41 (bs, 1H).

Example 15 4-Methyl-N-[5-(phenyl)-pyridine-2-yl]benzenesulfonamide

To a solution of 5-phenylpyridin-2-amine (340 mg, 2 mmol) in drypyridine (10 mL) was added 4-methylbenzenesulfonyl chloride (427 mg,2.24 mmol). The solution was stirred at room temperature under Argon.The pyridine was then removed in vacuo and flashed off with toluene. Theresidue was partitioned between EtOAc and 1M NaOH. The organic phase waswashed with 1M NaOH until no turbidity was observed on rectification ofa small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCland extracted with EtOAc. After drying over Na₂SO₄, solvent was removedin vacuo. The crude product weighed 0.24 g. The crude product was takenup in 10 mL of hot EtOAc, diluted with 10 mL of hexane and seeded togive 209 mg of white needles with mp 187-189° C.

¹H NMR (DMSO d₆) δ 2.33 (s, 3H), 7.20 (d, J=8.4 Hz, 1H), 7.32-7.45 (m,5H), 7.61 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 8.01 (bd, J=8.8 Hz,1H), 8.40 (bs, 1H), 11.65 (bs, 1H).

Example 163,4-Dimethoxy-N-[5-(4-chlorophenyl)-1,2,4-thiadiazol-3-yl]benzenesulfonamide

To a solution of 5-(4-chlorophenyl)-1,2,4-thiadiazol-3-amine (423 mg,2.0 mmol) in 10 mL of dry pyridine was added 529 mg (2.23 mmol) of3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at roomtemperature under Argon. After 21 h, the pyridine was removed in vacuoand flashed off with toluene. The residue was partitioned between EtOAcand 1M NaOH. The organic phase was washed with 1M NaOH until noturbidity was observed on rectification of a small sample. The alkalinephase was made acidic (˜pH 3) with 1M HCl and extracted with EtOAc. EtOHwas used in the second extraction to assist solubilizing thesulfonamide. After drying over Na₂SO₄, solvent was removed in vacuo. Thecrude crystalline product weighed 0.45 g. The crude product was taken upin 13 mL of hot HOAc, diluted with 7 mL of H₂O and seeded to give whiteneedles (384 mg) after collection by filtration, washing with H₂O, anddrying in vacuo. The product had mp 220-221° C.

¹H NMR (DMSO d₆) δ 3.39 (s, 3H), 3.80 (s, 3H), 7.13 (d, J=8.4 Hz, 1H),7.51 (d, J=2.0 Hz, 1H), 7.61 (dd, J=2.0, 8.4 Hz, 1H), 7.62 (d, J=8.4 Hz,2H), 7.91 (d, J=8.4 Hz, 2H), 12.22 (bs, 1H)

¹³C NMR (DMSO d₆) δ 55.735, 55.834, 110.211, 111.054, 121.579, 128.117,128.732, 129.651, 131.033, 137.176, 148.247, 152.606, 162.106, 180.261.

Example 17 3,4-Dimethoxy-N-[biphenyl-4-yl]benzenesulfonamide

To a solution of biphenyl-4-amine (338 mg, 2 mmol) in 10 mL of drypyridine followed by 529 mg of 3,4-dimethoxybenzenesulfonyl chloride.The solution was stirred at room temperature under Argon. After 21 h,the pyridine was removed in vacuo and flashed off with toluene. Theresidue was partitioned between EtOAc and 1M NaOH. The organic phase waswashed with 1M NaOH until no turbidity was observed on rectification ofa small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCland extracted with EtOAc. After drying over Na₂SO₄, solvent was removedin vacuo. The crude product (0.79 g) was obtained as a glass whichslowly crystallized. Addition of hexane caused complete solidification.The solid was taken up in EtOAc (11 mL), diluted with hexane (11 mL) andseeded to give 534 mg of white needles. The product had mp 171-173° C.

¹H NMR (DMSO d₆) δ 3.74 (s, 3H), 3.77 (s, 3H), 7.05 (d, J=8.5 Hz, 1H),7.18 (d, J=8.8 Hz, 2H), 7.27(d, J=2.0 Hz, 1H), 7.30 (t, J=7.2 Hz, 1H),7.35 (dd, J=2.0, 8.5 Hz, 1H), 7.40 (t, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.56(d, J=8.0 Hz, 2H), 10.19 (bs, 1H).

Example 183,4-Dimethoxy-N-[5-(3-nitrophenyl)-1,2,4-triazol-3-yl]benzenesulfonamide

Step 1: 3-Nitrobenzoyl chloride (10, 1.00 g, 5.39 mmol) andthiosemicarbazide (11, 0.49 g, 5.39 mmol) were added to phosphorusoxychloride (15 mL) and the mixture was heated at reflux temperature for3 h. The reaction mixture was carefully poured into cold water and theprecipitated solid was collected by filtration, washed with ether anddried in vacuo to give a mixture of the aminotriazole 12 and thethiadiazole 13, which was used as such for the preparation of 15.

Step 2: 3,4-Dimethoxybenzenesulfonyl chloride (14, 0.260 g, 1.13 mmol)was added to a stirred solution of the above mixture of 12 and 13 (0.500g) at room temperature and in a nitrogen atmosphere. After 8 h, thereaction mixture was diluted with toluene and then the solvents wereremoved in vacuo. The residue was partitioned between ethyl acetate andwater, the organic phase was dried over anhydrous sodium sulfate, andthe solvent was removed in vacuo to give a solid (0.120 g).

¹H NMR (CD₃OD) δ 3.93 (s, 6H), 6.64 (s, 1H), 7.10 (d, 1H, J=8.8 Hz),7.42 (bs, 1H), 7.56 (d, 1H, J=8.1 Hz), 7.81 (t, 1H, J=7.5 Hz), 8.23 (d,1H, J=7.5 Hz), 8.41 (d, 1H, J=7.5 Hz), 8.69 (bs, 1H); MS-ESI m/e 423(MH)⁺.

Example 194-Methyl-N-[5-(3-nitrophenyl)-1,2,4-triazol-3-yl]benzenesulfonamide

Same procedure as example 21 except that 4-methylbenzenesulfonylchloride is used instead of 3,4-dimethoxybenzenesulfonyl chloride.

Compound is a white solid. ¹H NMR (CD₃OD) δ 2.45 (s, 3H), 7.42 (d, 2H,J=8.8 Hz), 7.82 (t, 1H, J=7.9 Hz), 7.84 (d, 2H, J=8.8 Hz), 8.24 (d, 1H,J=8.1 Hz), 8.43 (d, 1H, J=7.7 Hz), 8.70 (bs, 1H); MS-ESI m/e 377 (MH)⁺.

Analogously, following compounds in the Table were also prepared:

Compound Compound name A3  3,4-dimethoxy-N-[3-(3-nitrophenyl)-1,2,4-thiadiazole-5-yl]benzenesulfonamide A4 4-methyl-N-[3-(3-nitrophenyl)-1,2,4- thiadiazole-5-yl[benzenesulfonamideA5  3,4-dimethoxy-N-[5-(phenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide A6 4-methyl-N-[5-(phenyl)-1,3,4-thiadiazol- 2-yl]benzenesulfonamide A7 3,4-dimethoxy-N-[5-(3-nitrophenyl)-1,3,4-thiadiazole-2-yl]benzenesulfonamide A8 4-methyl-N-[5-(3-nitrophenyl)-1,3,4- thiadiazole-2-yl]benzenesulfonamideA11 3,4-Dimethoxy-N-[5-(3-nitrophenyl)-1,2,4-triazol-3-yl]benzenesulfonamide A124-Methyl-N-[5-(3-nitrophenyl)-1,2,4- triazol-3-yl]benzenesulfonamide A203,4-dimethoxy-N-[5-(3-nitrophenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide A213,4-dimethoxy-N-[5-(phenyl)-1,2,4- thiadiazole-3-yl]benzenesulfonamide

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention.

1. A method for inhibiting activity of kynurenine-3-monooxygenase whichmethod comprises contacting a cell with an effective amount of one ormore compounds of Formula II:

wherein: T and W independently are selected from the group consisting ofN, NR³, S, S(O), S(O)₂, O, and CR³ and U is selected from the groupconsisting of N, NR³, S, S(O), S(O)₂, and O with the proviso that nomore than one of T, U, and W are S, S(O), S(O)₂, and O; R¹ and R²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, amino, substituted amino,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl,carboxyl ester, cyano, halo, hydroxyl, acyl, nitro, mercapto, alkylthio,substituted alkylthio, substituted sulfonyl, substituted sulfonyloxy,substituted sulfinyl, and aminocarbonyl, or R¹ and R² join together toform a ring selected from the group consisting of C₅-C₇ cycloalkyl,substituted C₅-C₇ cycloalkyl, C₅-C₇ heterocycloalkyl, substituted C₅-C₇heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; R³ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, halo, amino, substitutedamino, alkylthio, substituted alkylthio, substituted sulfonyl,substituted sulfinyl, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; R⁴ and R⁵ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, substituted amino, aminosulfonyl, aminosulfonyloxy,aminosulfonylamino, amidino, carboxyl, carboxyl ester, cyano, halo,hydroxyl, acyl, nitro, mercapto, alkylthio, substituted alkylthio,substituted sulfonyl, substituted sulfonyloxy, substituted sulfinyl, andaminocarbonyl, or R⁴ and R⁵ join together to form a ring selected fromthe group consisting of C₅-C₇ cycloalkyl, substituted C₅-C₇ cycloalkyl,C₅-C₇ heterocycloalkyl, substituted C₅-C₇ heterocycloalkyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl; and R⁶ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;or its tautomer and/or a pharmaceutically acceptable salt thereof, withthe proviso that the ring comprising U, W, and T is not1,3-thiazol-2-yl.
 2. The method according to claim 1, wherein the group

is thiadiazole.
 3. A method for treating a disease mediated at least inpart by kynurenine-3-monooxygenase which method comprises administeringto a patient an effective amount of one or more of a compound of FormulaII:

wherein: T and W independently are selected from the group consisting ofN, NR³, S, S(O), S(O)₂, O, and CR³ and U is selected from the groupconsisting of N, NR³, S, S(O), S(O)₂, and O with the proviso that nomore than one of T, U, and W are S, S(O), S(O)₂, and O; R¹ and R²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, amino, substituted amino,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl,carboxyl ester, cyano, halo, hydroxyl, acyl, nitro, mercapto, alkylthio,substituted alkylthio, substituted sulfonyl, substituted sulfonyloxy,substituted sulfinyl, and aminocarbonyl, or R¹ and R² join together toform a ring selected from the group consisting of C₅-C₇ cycloalkyl,substituted C₅-C₇ cycloalkyl, C₅-C₇ heterocycloalkyl, substituted C₅-C₇heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; R³ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, halo, amino, substitutedamino, alkylthio, substituted alkylthio, substituted sulfonyl,substituted sulfinyl, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; R⁴ and R⁵ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, substituted amino, aminosulfonyl, aminosulfonyloxy,aminosulfonylamino, amidino, carboxyl, carboxyl ester, cyano, halo,hydroxyl, acyl, nitro, mercapto, alkylthio, substituted alkylthio,substituted sulfonyl, substituted sulfonyloxy, substituted sulfinyl, andaminocarbonyl, or R⁴ and R⁵ join together to form a ring selected fromthe group consisting of C₅-C₇ cycloalkyl, substituted C₅-C₇ cycloalkyl,C₅-C₇ heterocycloalkyl, substituted C₅-C₇ heterocycloalkyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl; and R⁶ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl; substituted aryl, heteroaryl and substituted heteroaryl; orits tautomer and/or a pharmaceutically acceptable salt thereof; with theproviso that the ring comprising U, W, and T is not 1,3-thiazol-2-yl. 4.The method according to claim 3 wherein the compound is of Formula IIaor its tautomer and/or a pharmaceutically acceptable salt thereof:

wherein X is S or NR⁹ where R⁹ is alkyl or substituted alkyl; and R¹,R², R⁴, R⁵, and R⁶ are as defined in claim
 3. 5-6. (canceled)
 7. Themethod according to claim 4, wherein R¹ and R² independently areselected from the group consisting of hydrogen, nitro, trifluoromethyl,cyano, and halo.
 8. The method according to claim 4, wherein R⁴ and R⁵independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, and substituted alkoxy.
 9. The methodaccording to claim 4, wherein R⁶ is hydrogen. 10-14. (canceled)
 15. Themethod according to claim 3 wherein the compound is of Formula IIb orits tautomer and/or a pharmaceutically acceptable salt thereof:

wherein X¹ is S or NH; and R¹, R⁴, R⁵, and R⁶ are as defined in claim 3.16-17. (canceled)
 18. The method according to claim 15, wherein R¹ andR² independently are selected from the group consisting of hydrogen,nitro, trifluromethyl, cyano, and halo.
 19. The method according toclaim 15, wherein R⁴ and R⁵ independently are selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, andsubstituted alkoxy.
 20. The method according to claim 15, wherein R⁶ ishydrogen. 21-25. (canceled)
 26. The method according to claim 3 whereinthe compound is of Formula IIc or its tautomer and/or a pharmaceuticallyacceptable salt thereof:

wherein X² is O or NR⁹ where R⁹ is alkyl or substituted alkyl; and R¹,R², R⁴, R⁵, and R⁶ are as defined in claim
 3. 27-36. (canceled)
 37. Themethod according to claim 3 wherein the compound is of Formula IId orits tautomer and/or a pharmaceutically acceptable salt thereof:

wherein X³ is S or NR⁹ where R⁹ is alkyl or substituted alkyl; and R¹,R², R⁴, R⁵, and R⁶ are as defined in claim
 3. 38-39. (canceled)
 40. Themethod according to claim 37, wherein R¹ and R² independently areselected from the group consisting of hydrogen, nitro, trifluoromethyl,cyano, and halo.
 41. The method according to claim 37, wherein R⁴ and R⁵independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, and substituted alkoxy.
 42. The methodaccording to claim 37, wherein R⁶ is hydrogen. 43-44. (canceled)
 45. Themethod according to claim 3, wherein the compound is selected from thegroup consisting of3,4-dimethoxy-N-[3-phenyl-1,2,4-thiadiazol-5-yl]benzenesulfonamide;4-methyl-N-[3-phenyl-1,2,4-thiadiazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-[3-(3-nitrophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;4-methyl-N-[3-(3-nitrophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-(1-methyl-3-phenyl-1,2,4-triazol-5-yl)benzenesulfonamide;4-methyl-N-(1-methyl-3-phenyl-1,2,4-triazol-5-yl)benzenesulfonamide;3,4-dimethoxy-N-[3-(phenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;4-methyl-N[3-(phenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-[3-(3-nitrophenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;4-methyl-N-[3-(3-nitrophenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-[5-(phenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;4-methyl-N-[5-(phenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;3,4-dimethoxy-N-[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;4-methyl-N-[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;3,4-dimethoxy-N[3-(phenyl)-isoxazol-5-yl]benzenesulfonamide;4-methyl-N[3-(phenyl)-isoxazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-[1-methyl-3-phenyl-pyrazol-5-yl]benzenesulfonamide;4-methyl-N-[1-methyl-3-phenyl-pyrazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-[5-(4-chlorophenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide;3,4-dimethoxy-N-[5-(3-nitrophenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide;and3,4-dimethoxy-N-[5-(phenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide.46-60. (canceled)
 61. The method according to claim 3, wherein the group

is thiadiazole.
 62. The method according to claim 1, where in thecompound is selected from the group consisting of3,4-dimethoxy-N-[3-phenyl-1,2,4-thiadiazol-5-yl]benzenesulfonamide;4-methyl-N-[3-phenyl-1,2,4-thiadiazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-[3-(3-nitrophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;4-methyl-N-[2-(3-nitrophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-(1-methyl-3-phenyl-1,2,4-triazol-5-yl)benzenesulfonamide;4-methyl-N-(1-methyl-3-phenyl-1,2,4-triazol-5-yl)benzenesulfonamide;3,4-dimethoxy-N-[3-(phenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;4-methyl-N[3-(phenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-[3-(3-nitrophenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;4-methyl-N-[3-(3-nitrophenyl)-1,2,4-triazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-[5-(phenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;4-methyl-N-[5-(phenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;3,4-dimethoxy-N-[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;4-methyl-N-[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide;3,4-dimethoxy-N[3-(phenyl)-isoxazol-5-yl]benzenesulfonamide;4-methyl-N[3-(phenyl)-isoxazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-[1-methyl-3-phenyl-pyrazol-5-yl]benzenesulfonamide;4-methyl-N-[1-methyl-3-phenyl-pyrazol-5-yl]benzenesulfonamide;3,4-dimethoxy-N-[5-(4-chlorophenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide;3,4-dimethoxy-N-[5-(3-nitrophenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide;3,4-dimethoxy-N-[5-(phenyl)-1,2,4-thiadiazole-3-yl]benzenesulfonamide.